1. Field of the Invention (Technical Field)
The present invention relates to a method and multiple agents for treatment of sexual dysfunction, including male erectile dysfunction, including separate and preferably sequential administration of a melanocortin 3 and/or 4 receptor agonist, such as Ac-Nle-cyclo(-Asp-His-D-Phe-Arg-Trp-Lys)-OH (PT-141), preferably by one route of administration, such as intranasal (IN), and a type V phosphodiesterase (PDE-5) inhibitor, such as Viagra®, a trademark for a brand of sildenafil, preferably by another route of administration, such as oral.
2. Description of Related Art
Note that the following discussion refers to a number of publications by author(s) and year of publication, and that due to recent publication dates certain publications are not to be considered as prior art vis-a-vis the present invention. Discussion of such publications herein is given for more complete background and is not to be construed as an admission that such publications are prior art for patentability determination purposes.
In the medical and pharmaceutical arts, any of a variety of drugs are known for treatment of sexual dysfunction such as male erectile dysfunction. One known class of drugs are PDE-5 inhibitors. PDE-5 inhibitors include Viagra®, a brand of sildenafil, Levitra®, a brand of monohydrochloride salt of vardenafil, and Cialis®, a brand of tadalafil, among pharmaceutical products approved by the U.S. Food and Drug Administration, as well as a number of other compounds. In general, PDE-5 inhibitors increase the persistence of cyclic guanosine monophosphate in the corpus cavernosum, thereby enhancing erectile response.
Another class of drugs are agonists of the melanocortin receptor, such as those disclosed in the following publications, which are incorporated here by reference in their entirety: M. E. Hadley et al., Discovery and development of the novel melanogenic drugs, in Integration of Pharmaceutical Discovery and Development: Case Studies, edited by Borchardt et al., Plenum Press, New York (1998); R. T. Dorr et al., Evaluation of Melanotan-II, A Superpotent Cyclic Melanotropic Peptide in a Pilot Phase-I Clinical Study. Life Sci. 58:1777–1784 (1996); L. H. T. Van der Ploeg etr al., A Role for the Melanocortin 4 Receptor in Sexual Function. P.N.A.S., 99:11381–11386 (2002). The agonists can be melanocortin stimulation hormone (MSH), including α-, β-, and γ-MSH, or adrenocorticotropin (ACTH). Melanocortin receptor-specific compounds have been explored for use of treatment of sexual dysfunction. In one report, a cyclic α-melanocyte-stimulating hormone (“α-MSH”) analog, called Melanotan-II or MT-II, was evaluated for erectogenic properties for treatment of men with psychogenic and organic erectile dysfunction. H. Wessells et al., J. Urology 160:389–393 (1998), H. Wessells et al., Urology 56:641–646 (2000), and H. Wessells et al., Intl. J. Impotence Res. 12:S74–S79 (2000); see also U.S. Pat. No. 5,576,290, issued Nov. 19, 1996 to M. E. Hadley, entitled Compositions and Methods for the Diagnosis and Treatment of Psychogenic Erectile Dysfunction and U.S. Pat. No. 6,051,555, issued Apr. 18, 2000, also to M. E. Hadley, entitled Stimulating Sexual Response in Females. The peptides used in U.S. Pat. Nos. 5,576,290 and 6,051,555 are also described in U.S. Pat. No. 5,674,839, issued Oct. 7, 1997, to V. J. Hruby, M. E. Hadley and F. Al-Obeidi, entitled Cyclic Analogs of Alpha-MSH Fragments, and in U.S. Pat. No. 5,714,576, issued Feb. 3, 1998, to V. J. Hruby, M. E. Hadley and F. Al-Obeidi, entitled Linear Analogs of Alpha-MSH Fragments. Additional related peptides are disclosed in U.S. Pat. Nos. 5,576,290, 5,674,839, 5,714,576 and 6,051,555. Other peptides are described in a number of publications, including U.S. Pat. Nos. 6,350,430, 6,608,082 and 6,613,874. These peptides are described as being useful for both the diagnosis and treatment of psychogenic and organic sexual dysfunction in males and females. These peptides are related to the structure of melanocortin specific peptides.
A preferred melanocortin receptor agonist is Ac-Nle-cyclo(-Asp-His-D-Phe-Arg-Trp-Lys)-OH, called PT-141, as disclosed in U.S. Pat. Nos. 6,579,968 and 6,794,489, incorporated herein by reference. It is believed that melanocortin agonists, including PT-141, amplify the release of nitric oxide from nitrergic nerve fibers, and the cavernosal nerve in particular, enhancing erectile response by enhancing normal central and peripheral reflex pathways. R. Vemulapalli et al., Activation of Central Melanocortin Receptors by MT-II Increases Cavernosal Pressure in Rabbits by the Neuronal Release of NO. British Journal of Pharmacology, 134:1705–1710 (2001). Other preferred melanocortin receptor agonists are disclosed in U.S. patent application Ser. No. 10/638,071, published as U.S. Patent Application Publication No. 20040138136 A1, entitled “Cyclic Peptide Compositions and Methods for Treatment of Sexual Dysfunction,” incorporated herein by reference.
Combination therapy, particularly with PDE-5 inhibitors such as sildenafil, has been considered for a number of years. For example, one article proposes combination therapy of intraurethral prostaglandin E1 and sildenatil (A. Nehra et al., Rationale for Combination Therapy of Intraurethral Prostaglandin E1 and Sildenafil in the Salvage of Erectile Dysfunction Patients Desiring Noninvasive Therapy. Int'l Journal of Impotence Research, 14(S1):S38–S42 (2002)), another article describes potential combinations with α-andrenoceptor antagonists or testosterone replacement therapy (F. Sommer and U. Engelmann, Future Options for Combination Therapy in the Management of Erectile Dysfunction in Older Men. Drugs and Aging, 9:555–564 (2004). WO 00/53148 (Merck) discloses and claims a “method for the treatment of erectile dysfunction which comprises administering to a human subject in need of such treatment an effective amount of an agonist of the melanocortin receptor in combination with an effective amount of a cyclic-GMP-specific phosphodiesterase inhibitor or an alpha-andrenergic receptor antagonist.” MT-II is a disclosed melanocortin receptor agonist and sildenafil is a disclosed PDE-5 inhibitor. The entire application is prophetic; that is, there is no actual data reported or disclosed. Hypothetical formulations disclosed include, for example, 5 mg of a melanocortin agonist and 10 mg of a PDE-5 inhibitor combined together in a capsule. The Merck application does not disclose intranasal administration of MT-II. Additionally, the Merck application does not disclose that a peptide-based melanocortin agonist may be administered by an intranasal route and a PDE-5 inhibitor administered by an oral route, or that the agents may be sequentially administered at timed intervals to obtain optimal results. Nor does the application disclose a synergistic effect, such as by administering a sub-therapeutic dose of each agent, which nonetheless results in a desired therapeutic result.
WO 02/069905 and United States Patent Application US 2003/0069169 disclose a “method of regulating . . . cAMP production in a mammal comprising administering . . . a combination of (i) an amount of at least one compound effective for agonizing a melanocortin-receptor selected from MC-1R and MC-4R, and (ii) an amount of at least one compound effective for inhibiting cAMP phosphodiesterase.” Specific disclosures are only to PDE-3, -4, -7 or -8 inhibitors, and a number of specific diseases are disclosed (e.g., inflammatory bowel disease, rheumatoid arthritis, asthma, etc.), but not sexual dysfunction. Again, there is only disclosure of “combination” drug, that is, a single pharmaceutical preparation including both a melanocortin receptor agonist and a PDE inhibitor.
A number of other patents and patent applications contain prophetic disclosures of combination therapy where one agent is a melanocortin receptor agonist and a second agent is a PDE-5 inhibitor; representative examples include U.S. Pat. No. 6,894,040 (disclosing administering a xanthine phosphodiesterase V inhibitor as “combination therapy” with any of a long list of agents including a melanocortin receptor agonist); U.S. Pat. No. 6,376,509 (disclosing a small molecule asserted to be a melanocortin receptor agonist in a pharmaceutical composition including a PDE-5 inhibitor); U.S. Published Patent Application 2004/0192676 (disclosing a small molecule asserted to be a melanocortin receptor agonist in a pharmaceutical composition including sildenafil); U.S. Published Patent Application 2004/0266821 (disclosing an acylated piperidine derivative asserted to be a melanocortin receptor agonist in combination with a PDE-5 inhibitor such as sildenafil); and U.S. Published Patent Application 2005/0075344 (disclosing a small molecule asserted to be a melanocortin receptor agonist in combination with a PDE-5 inhibitor such as sildenafil). U.S. Published Patent Application 2004/0208829 discloses an aerosol formulation to be inhaled into a patient's lungs; in one embodiment there is disclosed an aerosol formulation including an active ingredient selected from one or more of a lengthy list of agents, which agents include PDE-5 inhibitors and a melanocortin receptor agonist. Each of the foregoing are, with respect to any combination therapy or formulation, merely prophetic, and do not include any clinical or animal study data.
It is well recognized that PDE-5 inhibitors, such as sildenafil, vardenafil or tadalafil, can have adverse side effects, such as headache, facial flushing, nasal congestion, changes in vision and the like. U. Gresser and C. H. Gleiter, Erectile Dysfunction: Comparison of Efficacy and Side Effects of the PDE-5 Inhibitors Slidenafil, Vardenafil and Tadalafil, Review of the Literature. European J. of Med. Res., 7:435–446 (2002). Side effects and other adverse events are generally dose dependent, with increasing frequency and severity at higher doses. This results in discontinuation of use of PDE-5 inhibitors by patients over time. P. C. Souverein et al., Incidence and Determinants of Sildenafil (dis)continuation: the Dutch Cohort of Sildenafil Users. Int. J. Impot. Res. 14:259–265 (2002). Similar dose dependent side effects and adverse events results from IN PT-141 administration. L. E. Diamond et al., Double-blind, Placebo-Controlled Evaluation of the Safety, Pharmacokinetic Properties and Pharmacodynamic effects of Intranasal PT-141, a Melanocortin Receptor Agonist, in Healthy Males and Patients with Mild-to-Moderate Erectile Dysfunction. Int. J. Impot. Res. 16:51–59 (2004). Thus there is a need for a therapeutic method for treatment of erectile dysfunction in males, and sexual dysfunction generally, which results in desired efficacy, without limiting side effects and other adverse events. It is against this background that the invention was made.